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Introduction to clinical trials 2012-01-26 Stefan Franzén Definition of a clinical trial A research activity that involves administration of a test treatment to some experimental unit in order to evaluate the treatment. Key words Treament Experimental unit Evaluate Pharmaceutical, diet, procedure, diagnostic, device, program, placebo. Subject from a target population. Assessment of (clinical) effect, but also adverse events, lab variables, vital signs, quality of life, health economy. The first study I have found two treats that makes a letcure seem more interesting. How do I find out which one is best? The Wheel of Science Experiment Research question Data Conlusion Drug discovery/development process discovery; refinement; chemical & biological characterisation safety & toxicity in animals; formulation development volunteer studies; patient studies regulatory process marketing Lessons & development post registration monitoring Discovery=find new active structure : Development=convert it to a useful drug The path to a new medicine Years 1 2 3 4 First patent application Drug Discovery Target and lead Lead identification optimisation 5 6 7 8 9 Clinical trial application 10 12 13 14 15 Product licence application Drug Development Development Concept testing for launch Clinical Phase I 12-150 people 11 Development Phase II Phase III 50-1000 500-5,000 people people Product life Launch cycle support Phase IV studies continue Toxicology and pharmacokinetic studies (absorption, distribution, metabolism, excretion) Pharmaceutical and analytical development Process chemistry and manufacturing Registration and regulatory affairs Sales and marketing (preparation, promotion, advertising and selling) No. of compounds Up to 10,000 10-15 1-8 1-3 1 16 Phase I trials Phase I 50-150 people • • • • • • • • Phase II 100-200 people Phase III 500-15000 people Phase IV studies continue Focused on tolerability and safety 12-30 (150) healthy people (often males) Efficacy on biomarkers Single and repeated doses Increase dose levels Interaction with other drugs Pharmacokinetics Explorative Phase 2 trials Phase I 50-150 people • • • • • • • • Phase II Phase III 50-1000 500-5,000 people people Phase IV studies continue 50-1000 patients Extensive monitoring Safety and tolerability in patients Often complicated design, explorative Selection of optimal dose Pharmacokinetics in patients Effect in special populations Explorative Phase 3 trials Phase I 50-150 people • • • • Phase II 100-200 people Phase III 500-15000 people Phase IV studies continue 500-15000 patients Effect is verified in the target population Forms the basis of the NDA, New Drug Application Interactions between drugs start to become measurable in the larger population • sub-groups start to be established • special features and problems show up • Confirmative Phase IV trials Phase I 50-150 people Phase II 100-200 people Phase III 500-5,000 people Phase IV studies continue • Often large 500-15000 patients • Further investigation of efficacy and safety post approval • Special populations • New indications • Marketing Observational studies Data is collected for a set of patients without any randomisation Prospective: Data is collected after the objectives are set data collection analysis interpretation time now Retrospective: Data is collected before the objectives are set data collection analysis now interpretation time Where to look for information ICH (international Conference on Harmonisation) http://www.ich.org/products/guidelines.html FDA (Food and Drug Agency) http://www.fda.gov/ EMEA (European Medicines Agency) http://www.emea.europa.eu/ Cochrane Collaboration http://www.cochrane.org/index.htm The Clinical Study Process Preparation of statistical analysis Outline Clinical Study Protocol Study Conduct Study Setup Statistical Analysis Clinical Study Report Data Capture Publications Statistical Analysis Plan Clean File Data base lock Time Chapter 1 Reading instructions • • • • • • • 1.1 What are clinical trials: Read 1.2 History of clinical trials: Less important 1.3 Regulatory process and requirements: Read page 14 1.4 Investigational new drug application: Read page 17–20 1.5 New drug application: Less important 1.6 Clinical development plan and practise: Read 1.7 Aims and structure of this book: Skip